Fused bicyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors

Abstract

The present invention is directed to novel bicyclic heterocycles of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

What is claimed is: 
     
       1. A compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein X 1  and X 2  are independently selected from the group consisting of —N— and —CR 5 —;
 R 1  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heterocycle, aroyl, heteroaroyl and C 3 -C 10 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heterocycle, aroyl, heteroaroyl and C 3 -C 10 cycloalkyl are unsubstituted or substituted with 1-3 substituents from R 5 ; 
 R 2  is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, heterocycle and C 1 -C 6 alkylheterocycle; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, heterocycle and C 1 -C 6 alkylheterocycle are unsubstituted or substituted with 1-3 substituents each independently selected from R 3 , R 4  and R 5 ; 
 R 3  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and aryl, wherein the C 1 -C 6 alkyl and aryl are unsubstituted or substituted with 1-3 substituents selected from R 5 ; 
 R 4  is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; 
 R 5  is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, halogen-substitutedC 1 -C 6 alkyl, —OH, C 1 -C 6 alkylOH, halogen-substitutedC 1 -C 6 alkylOH, —OC 1 -C 6 alkyl, —Ohalogen-substitutedC 1 -C 6 alkyl, —COOH, —COOC 1 -C 6 alkyl, —C 1 -C 6 alkylCOOC 1 -C 6 alkyl, —C 1 -C 6 alkylCOOH, —CN, C 1 -C 6 alkylCN, NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkylCONH 2 , —CONH 2 , —CONHC 1 -C 6 alkyl, —NHCOC 1 -C 6 alkyl, —CON(C 1 -C 6 alkyl) 2 , —NHSO 2 C 1 -C 6 alkyl, SO 2 aryl, —SO 2 C 1 -C 6 alkyl, C 1 -C 6 alkylSO 2 C 1 -C 6 alkyl, aryl, —NHCOaryl, and —NHCOheterocycle; and 
 n is 0-4. 
 
     
     
       2. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein X 1  is —N— and X 2  is —CR 5 —. 
     
     
       3. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein X 1  and X 2  are —N—. 
     
     
       4. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 1  is heterocycle. 
     
     
       5. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 1  is hydrogen. 
     
     
       7. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 1  is C 1 -C 6 alkyl. 
     
     
       8. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein n is 1. 
     
     
       9. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       10. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 2  is selected from the group consisting of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and benzyl, wherein C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and benzyl are unsubstituted or substituted with 1-3 substituents selected from R 5 . 
     
     
       11. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 2  is selected from the group consisting of 2-butynyl, 2,5-difluorobenzyl, 2,4,5-trifluorobenzyl, 2-cyanobenzyl, 2-cyano-5-fluorobenzyl, 2-cyano-4,5-difluorobenzyl, 2,4-dichlorobenzyl 2,5-dichlorobenzyl, and 2-bromo-5-fluorobenzyl. 
     
     
       12. The compound of  claim 1  or pharmaceutically acceptable salt thereof wherein R 5  is selected from the group consisting of hydrogen, halogen, and —CN. 
     
     
       13. A compound of structural formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salts thereof; wherein X 1 , X 2 , n, R 1 , R 2  and R 5  are as described in  claim 1 . 
     
     
       14. A compound or pharmaceutically acceptable salt, selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       15. A pharmaceutical composition which comprises a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       16. The pharmaceutical composition of  claim 15  additionally comprising a second agent selected from the group consisting of metformin, pioglitazone, rosiglitazone, a sulfonylurea, and an HMG-CoA reductase inhibitor. 
     
     
       17. A method of treating a condition selected from the group consisting of insulin resistance, hyperglycemia, and Type 2 diabetes by administering a therapeutically effective amount of a compounds of  claim 1 , or a pharmaceutically acceptable salt thereof to a patient in need thereof.